Abstract. –OBJECTIVE: To investigate the ef- fects of N-acetylcysteine (NAC) on pulmonary function tests and arterial blood gases in patients undergoing on-pump coronary artery surgery.
PATIENTS AND METHODS:The effect of NAC was assessed within the scope of a prospec- tive, single center, double-blind, placebo-con- trolled, parallel group study. Eighty-two patients undergoing coronary artery bypass grafting were randomized into two groups to receive ei- ther placebo (group 1, n = 40) or NAC (group 2, n=42). Both the NAC group and the placebo-re- ceiving control group also included a COPD subgroup consisting of patients with an FEV1/FVC ratio of < 0.7 and an FEV1value of 50- 80%. Pulmonary function tests were performed preoperatively and on postoperative day 60.
RESULTS: Both groups were similar with re- spect to age, gender, preoperative risk factors, ejection fraction (EF), mean cross-clamp time, ventilation time, intensive care unit (ICU) stay, atrial fibrillation (AF) and hospital stay (p> 0.05).
Postoperative FVC and FEV1 values in group 1 and the postoperative FEV1, FEV1/FVC and FEF 25-75 values in group 2 were lower in compari- son to their preoperative values. However, in both group 1 and 2, the decreases observed in these parameters were not statistically signifi- cant (p> 0.05). In the COPD subgroup of group 1, a postoperative decrease was observed in the FEV1 and FEF25-75 values, with the FEV1 de- creasing by 4.55%, and the FEF25-75 decreasing by 4.2% (p < 0.05). In the COPD subgroup of group 2, no significant decrease was observed in the pulmonary function test values (p> 0.05).
The effects of N-acetylcysteine on
pulmonary functions in patients undergoing on-pump coronary artery surgery:
a double blind placebo controlled study
N. ERDIL, T. EROGLU
1, B. AKCA
2, O.M. DISLI, O. YETKIN
3, M.C. COLAK, F. ERDIL
4, B. BATTALOGLU
Department of Cardiovascular Surgery, Turgut Özal Medical Center, Inönü University Faculty of Medicine, Malatya, Turkey
1Department of Cardiovascular Surgery, Kayseri State Hospital, Kayseri, Turkey
2Department of Cardiovascular Surgery, Kilis State Hospital, Kilis, Turkey
3Department of Pulmonary and Sleep Medicine, Turgut Özal Medical Center, Inönü University Faculty of Medicine, Malatya, Turkey
4Department of Anesthesiology and Reanimation, Turgut Özal Medical Center, Inönü University Faculty of Medicine, Malatya, Turkey
All authors were working at Inönü University Faculty of Medicine during the study period
CONCLUSIONS: This study demonstrated that NAC administration in COPD patients un- dergoing on-pump coronary artery surgery re- sulted in the preservation of pulmonary func- tions.
Key Words:
N-Acetylcysteine, Pulmonary function tests, Bypass surgery, Coronary artery.
Introduction
Pulmonary dysfunction is one of the most common and serious complications of cardiac surgeries performed with cardiopulmonary by- pass (CPB)1,2. The etiology of pulmonary dys- function is multifactorial: the condition can result from a combination of the effects of general anesthesia, surgical injury, median sternotomy and CPB. CPB is often associated with systemic inflammation, which generally develops as a re- sult of a CPB-induced postpump syndrome or systemic inflammatory response. Systemic in- flammatory response syndrome (SIRS) during cardiac surgery can result in four types of injury:
contact of the blood components with the artifi- cial surface of the bypass circuit, ischemia-reper- fusion injury, endotoxemia and operative trau- ma3.
SIRS can lead to post-cardiac surgery compli- cations such as myocardial injury, renal dysfunc- tion, atrial fibrillation (AF) and pulmonary in- jury4-8. Pulmonary injury observed during cardiac surgery is characterized by increased pulmonary vascular resistance (PVR), impaired gas ex- change, and decreased pulmonary mechanics9,10. It is believed that the administration of antioxi- dant and anti-inflammatory agents might poten- tially alleviate SIRS in patients undergoing on- pump coronary artery surgery.
NAC is a free radical scavenger that exhibits beneficial antiinflammatory and antioxidant ef- fects. NAC inhibits inducible nitric oxide syn- thase, suppresses cytokine expression/release, and inhibits the expression of adhesion mole- cules and of nuclear factor kappa B5,11-13.
The main purpose of our study was to investi- gate the effect of NAC administration on the postoperative pulmonary function tests and arter- ial blood gases of patients undergoing on-pump coronary artery surgery.
Patients and Methods
The study protocol was approved by the Ethics Committee of Inonu University Medical Faculty (number 2007/160). Written informed consent was obtained from all patients prior to the surgery. The effect of NAC was assessed within the scope of a prospective, single center, double-blind, placebo-controlled, parallel group study. The study was conducted prospec- tively with 82 patients who underwent coronary bypass surgery at our clinic between November 2007 and December 2008. The exclusion crite- ria of the study were emergency operations, significantly impaired ventricular function (ejection fraction < 40%), severely restricted or obstructed pulmonary functions and hemody- namic instability following revascularization.
The patients were divided into two groups, which were the placebo-receiving control group (group 1, n=40) and the NAC group (group 2, n=42). In group 2, NAC was adminis- tered preoperatively for 3 days at dose of 600 mg/day P.O., and 300 mg of NAC was added in the prime solution. Both the NAC group and the placebo-receiving control group also in- cluded a COPD subgroup consisting of COPD patients. Patients were considered as having COPD in case their FEV1/FVC ratio was < 0.7, and their FEV1value was between 50-80%.
Operative Procedure Anesthesia
All patients were monitorized following their transfer to the operation room. A pulse oximetry probe was attached to each patient in order to monitor peripheral arterial oxygen saturation. A 20 G branule was placed on the right radial artery to monitor systemic arterial pressure and arterial blood gas. Anesthesia was induced with a mixture consisting of 2% lidocaine (1 mg/kg), midazolam (0.2-0.3 mg/kg), fentanyl (5 µg/kg) and vecuronium (0.1 mg/kg). All patients were manually respirated, intubated after complete muscle relaxation, and connected to a mechani- cal ventilator. Anesthesia was maintained through the administration of a fentanyl (10-30 µg/kg) and midazolam (0.1-0.3 mg/kg/hour) mixture. For antibiotic prophylaxis, 1 g of cefa- zolin sodium was administered intravenously pri- or to the surgical procedures.
Surgical Technique
For both groups, coronary bypass grafting was performed with median sternotomy by using standard CPB procedure with single venous two- step right atrial and ascending aortic cannulation.
Mild systemic hypothermia (32°C) was induced and CPB was carried out using a disposable membrane oxygenator (Dideco Sorin Group, Mi- randola, Italy) and a roller pump (Cobe Cardio- vascular Inc., Avrada, CO, USA). Myocardial preservation was achieved with antegrade and retrograde infusion of cold blood cardioplegia, which was repeated every 20 minutes. Through- out the CPB procedure, the hematocrit level was maintained between 22-25%, and the mean arter- ial pressure was maintained between 50-70 mmHg. Heparin was provided for anticoagula- tion in order to ensure an active coagulation time
> 480s immediately before the CPB procedure.
Warm blood cardioplegia was given before re- moving the aortic cross-clamp. Internal mamma- ry artery (IMA) was preferred for Left Anterior Descending (LAD) artery anastomosis in all pa- tients. However, saphenous venous grafts were used in cases where IMA grafts were not suit- able. In suitable cases with multiple coronary artery disease, radial artery and/or saphenous ve- nous grafts were attached in addition to the IMA graft. Distal anastomoses were performed under cross-clamp with 7-8/0 prolene sutures, while proximal anastomoses were performed under
Group 1 (control) (n = 40) Group 2 (NAC) (n = 42) p value
Age (years) 58.8 ± 9.9 58.6 ± 10.1 0.927
Sex (female %) 6 (15%) 7 (16.7%) 0.836
Preoperative myocardial infarction 29 (74.4%) 30 (71.4%) 0.767
Vessel disease count
One vessel disease 2 (5%) – 0.235
Two vessel disease 25 (62.5%) 15 (35.7%) 0.015
Triple vessel disease 13 (32.5%) 27 (64.3%) 0.004
Left main disease – – –
Diabetes mellitus 8 (20,5%) 9 (22%) 0.875
Hypertension 15 (38.5%) 11 (26.8%) 0.267
Preoperative cerebrovascular disease 1 (2.5%) 2 (4.8%) 1.000
Current smoker 25 (64.1%) 26 (63.4%) 0.949
Family history 15 (38.5%) 13 (31.7%) 0.527
COPD (FEV1/FVC < 0.7) 3 (7.7%) 4 (9.8%) 0.744
Hypercholesterolemia 11 (27.5%) 15 (35.7%) 0.424
Peripheral vascular disease – – –
Carotid artery disease ≥ 20% 3 (7.5%) 3 (7.1%) 0.951
Preoperative PCI 4 (10%) 3 (7.1%) 0.643
Low left ventricular ejection fraction 4 (10%) 7 (16.7%) 0.376
EDP 9.4 ± 2.6 8.9 ± 3.1 0.476
Unstable angina 2 (5%) 3 (7.1%) 0.685
Obesity 5 (12.5%) 9 (21.4%) 0.283
Metabolic syndrome 14 (35%) 16 (38.1%) 0.771
Euroscore 3.4 ± 2.1 3.1 ± 2.2 0.585
BSA 1.8 ± 0.15 1.8 ± 0.16 0.954
BMI 26.3 ± 3,7 26.4 ± 3.9 0.831
Preoperative ejection fraction 48.5 ± 8.2 49.5 ± 7.9 0.609
Table I.Demographic and clinical characteristics of patients.
COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; EDP: end diastolic pressure; BSA:
body surface area; BMI: body mass index.
cross-clamp with 6/0 prolene sutures. Epicardial temporary pacing wires were routinely inserted.
The left pleura were opened routinely, and one of the drains was inserted in the left thorax while the other was inserted in the subxiphoid region.
At the end of the CPB procedure, protamine was administered to reverse the anticoagulative effect of heparin.
Pulmonary Function Tests and Blood Gas Analysis
Pulmonary function tests, which included as- sessments of forced expiratory volume in 1 sec- ond (FEV1), forced vital capacity (FVC) and forced midexpiratory volume (FEF25-75), were performed preoperatively and at postoperative day 60 by using a spirometer (Vmax 22 Sensor Medics, Yorba Linda, CA, USA).
Arterial blood gases were analyzed (Rapidlab Bayer Health Care, Germany) preoperatively and at postoperative days 2, 7 and 60 by radial punc- ture. Blood gas analysis included the assessment
of partial arterial oxygen pressure (PaO2), partial arterial carbon dioxide pressure (PaCO2) and ar- terial pH levels.
Statistical Analysis
Statistical analyses were performed using the SPSS 16.0 package program (SPSS Inc. Chica- go, IL, USA). Measurable data were provided as mean ± standard deviation (SD), while quali- tative data were provided as percentages. The Pearson chi-square and Fisher’s exact chi- square tests were used for comparing qualitative data. Measurable data were tested with the Shapiro-Wilk normality test, which indicated that the countable data displayed normal distrib- ution (p > 0.05). For this reason; two group mean comparisons were performed using the unpaired t test, while changes between the pre- operative and postoperative period in the para- meters used for evaluating pulmonary functions were evaluated using the paired t test. In both groups, the changes in blood gas levels were
tested using the repeated measures one-way analysis of variance. A p value < 0.05 was con- sidered as being statistically significant.
Results
Eighty two patients were randomized to two groups. The demographic and clinical character- istics of the patients are shown in Table I. There were no significant differences between the two groups with respect to age, gender, preoperative risk factors and ejection fraction (EF).
The preoperative and postoperative variables are shown in Table II. There were no significant differences between the two groups with respect to mean cross-clamp time, ventilation time, ICU stay, AF and hospital stay (p > 0.05).
The preoperative pulmonary function test and blood gas analysis variables did not differ signifi- cantly between the two groups (p > 0.05). The pul- monary function test results are shown in Table III.
The pulmonary function test results for the COPD subgroups are shown in Table IV, while the blood gas analysis results are shown in Table V.
Postoperative FVC and FEV1 values in group 1 and the postoperative FEV1, FEV1/FVC and
FEF 25-75 values in group 2 were lower in com- parison to their preoperative values. However, in both group 1 and 2, the decreases observed in these parameters were not statistically significant (p > 0.05).
In the COPD subgroup of group 1, a postoper- ative decrease was observed in the FEV1 and FEF25-75 values, with the FEV1 decreasing by 4.55%, and the FEF25-75 decreasing by 4.2% (p
< 0.05). In the COPD subgroup of group 2, no significant decrease was observed in the pul- monary function test values (p > 0.05).
During blood gas analysis, it was determined that the pO2values on postoperative day 2 were lower than the values observed preoperatively and on postoperative day 7 and 60 in both groups. The difference between these values was statically significant (p < 0.05).
Discussion
Cardiopulmonary bypass (CPB) is often asso- ciated with systemic inflammation, which gener- ally develops as a result of a CPB-induced post- pump syndrome or systemic inflammatory re- sponse. SIRS can lead to the development of
Group 1 (control) (n = 40) Group 2 (NAC) (n = 42) p value
LIMA used for CABG 39 (97.5%) 41 (97.6%) 0.972
Radial artery used for CABG 5 (12.5%) 6 (14.3%) 0.813
Number of grafts 2.62 ± 0.59 2.86 ± 0.78 0.134
Aortic cross-clamp time (min) 65.9 ± 15.7 74.5 ± 18.5 0.031
Perfusion time (min) 76.6 ± 16.9 84.4 ± 20.3 0,070
Inotropic support 2 (5%) 1 (2.4%) 0.611
IABP – – –
Ventilation time (h) 6.4 ± 2.3 6.5 ± 2.7 0.870
ICU stay (day) 2.5 ± 0.9 2.5 ± 0.6 0.952
Re-exploration for bleeding – – –
Atrial fibrillation 2 (5%) 7 (16.7%) 0.091
Hospital stay (day) 6.8 ± 1.3 6.5 ± 0.8 0.254
Postoperative cerebrovascular disease 1 (2.5%) – 0.488
Renal dysfunction – – –
GIS complications – – –
Total arterial revascularization 3 (7.5%) 4 (9.5%) 0.743
Defibrillation after cross-clamp 6 (15%) 8 (19%) 0.663
Superficial wound infection – 2 (4.8%) 0.494
Deep wound infection – – –
Pleural effusion 3 (7.5%) 2 (4.8%) 0.604
Persistent air leak – 1 (2.4%) 1.000
Subcutaneous emphysema – – –
Pneumonia – – –
Re-hospitalization 4 (10%) 2 (4.8%) 0.363
Table II.Preoperative and postoperative data.
LIMA: Left Internal Mammary Artery; ICU: Intensive Care Unit; GIS: Gastrointestinal System.
Group 1 (control, n = 40)Group 2 (NAC, n = 42) PreoperativePostoperativepvaluePreoperativePostoperativepvalue FVC (liters)3.58 ± 0.85 (100.04 ± 19.13%)3.34 ± 0.83 (93.7 ± 20.25%)0.010*3.74 ± 1.06 (100.05 ± 20.40%)3.61 ± 0.97 (100.01 ± 19.91%)0.090 FEV1(liters)2.64 ± 0.65 (94.75 ± 20.22%)2.43 ± 0.61 (85.3 ± 20.64%)0.004*2.86 ± 0.77 (100 ± 18.47%)2.68 ± 0.71 (94.96 ± 18.21%)0.001* FEV1/FVC (%)74.52 ± 11.0473.5 ± 11.320.22077.24 ± 7.6974.88 ± 7.230.021* FEF25-75 (liters/sec)2.17 ± 1.13 (68.7 ± 36.5%)1.99 ± 1.17 (59.9 ± 33.4%)0.1572.59 ± 1.09 (77.3 ± 29.9%)2.24 ± 1 (66.9 ± 27.1%)0.002*
Table III.Data on preoperative and postoperative pulmonary functions. FVC: Forced Vital Capacity; FEV1: Forced Expiratory Volume in 1 Second; FEF25-75: Forced Mid Expiratory Flow; *p< 0.05 compared with control group. Group 1 (control, n = 20)Group 2 (NAC, n = 10) PreoperativePostoperativepvaluePreoperativePostoperativepvalue FVC (liters)3.68 ± 0.61 (102.2 ± 47.2%)3.56 ± 0.72 (97.65 ± 16.8%5)0.1494.03 ± 0.96 (112.22 ± 22.92%)3.95 ± 0.83 (111.67 ± 26.42%)0.503 FEV1(liters)2.46 ± 0.48 (72.5 ± 7.72%)2.34 ± 0.58 (67.95 ± 8.22%)0.019*2.76 ± 0.63 (74.22 ± 10.83%)2.76 ± 0.52 (75.67 ± 14.9%)0.325 FEV1/FVC (%)65.1 ± 6.9264.25 ± 7.380.37866 ± 1.7667.30 ± 5.660.517 FEF25-75 (liters/sec)1.51 ± 0.53 (44.6 ± 13.06%)1.36 ± 0.54 (40.4 ± 13.71%)0.036*1.73 ± 0.35 (53.44 ± 12.82%)1.69 ± 0.29 (52.67 ± 10.64%)0.450 Table IV.Data on pulmonary functions in the COPD subgroup FVC: Forced Vital Capacity; FEV1: Forced Expiratory Volume in 1 Second; FEF25-75: Forced Mid Expiratory Flow; *p< 0.05 compared with control group.
post-cardiac surgery complications such as my- ocardial injury, renal dysfunction, AF and lung injury4-8. Experimental and clinical studies14-17 that attempt to reduce the appearance of SIRS fo- cus on blocking the activation of white blood cells, since many inflammatory mediators are be- lieved to exert their damaging effects through these cells3,14. Methods and approaches used in these studies to reduce SIRS occurrence include off-pump coronary surgery, changes in perfusion temperature, use of heparin bound surfaces, ul- trafiltration, leukocyte depletion, and the admin- istration of complement inhibitors, glucocorti- coids, aprotinin or NAC.
NAC is an effective antioxidant. NAC is a glu- tathione precursor that increases the levels of in- tracellular sulfhydryl18. Glutathione plays a cen- tral role in cellular defense against specific reac- tive oxygen species (ROS), and also acts at an extracellular level – either directly or via the glu- tathione peroxidase catalysis – to scavenge the generated ROS. NAC administration has the ef- fect of increasing glutathione levels and reducing oxidoinflammatory damage. These characteris- tics make NAC a potentially useful therapeutic option for preventing commonly encountered complications related to oxidoinflammatory damage.
Pulmonary injury associated with CPB is gen- erally characterized by increased PVR, impaired gas exchange and decreased pulmonary mechan- ics9,10. These effects are also observed during is- chemia-reperfusion injury. Angdin et al19demon- strated that, following the occurrence of CPB, patients treated with antioxidant agents such as vitamins C and E, allopurinol and NAC had bet- ter preservation of endothelial function than pa- tients treated with placebo. In addition, Karabay et al20 reported that NAC contributed to the preservation of pulmonary functions, and also al- lowed reduced pulmonary functions to recover more rapidly.
Eren et al21 previously evaluated the effects of NAC on the pulmonary functions of patients undergoing coronary artery bypass surgery with cardiopulmonary bypass. They reported in their study a significantly lower increase in postoper- ative A-a oxygen gradient and lower malondi- aldehyde increase in NAC-administered group.
In our study, we compared the pulmonary func- tions of patients in the NAC and control groups.
The pulmonary functions of the patients were evaluated using pulmonary function tests and arterial blood gas analysis. No significant dif-
Group 1 (control, n = 40)Group 2 (acetylcysteine, n = 42) Postop.PostopPostop.Postop.Postop.Postop. Preop.Day 2Day 7Day 60Preop.Day 2Day 7Day 60 pH7.44 ± 0.347.46 ± 0.057.47 ± 0.05*7.43 ± 0.04£7.44 ± 0.057.46 ± 0.03*7.48 ± 0.05*7.44 ± 0.03¥ pCO2(mmHg)35.15 ± 5.1235.15 ± 5.1233.85 ± 4.67£34.58 ± 3.9735.74 ± 4.0936.62 ± 4.2933.52 ± 4.66£34.14 ± 3.17£ pO2(mmHg)77.46 ± 14.5657.24 ± 8.54*70.36 ± 12.24£71.13 ± 12.73£77.75 ± 9.5858.62 ± 8.46*69.25 ± 7.67*,£72.86 ± 7.17*.£.¥
Table V.Arterial Blood gas analysis results. *Compared with Preoperative values p< 0.05. £Compared with Postoperative Day 2 values p< 0.05. ¥Compared with Postoperative Day 7 values p< 0.05.
ferences were observed between the NAC and control groups with respect to their pulmonary function tests and arterial blood gas analysis re- sults. However, we observed the preservation of pulmonary functions in the COPD subgroup of the NAC-administrated group (a 4.55% de- crease in FEV1, and a 4.2% decrease in FEF 25- 75 in the control group).
The milder side effects of NAC include clam- my skin, fever, increased lung mucous, and irri- tation/soreness in the mouth, throat, or lungs.
Uncommon side effects of NAC, which may re- quire immediate medical attention, include wheezing, tightness in the chest, difficulty breathing (especially among asthmatics), and skin rash or irritation. These rare side effects were not observed in any of our patients during the study.
The number of the patients in the COPD sub- group was relatively small in this study; there- fore, to be able to validate the beneficial effects of NAC administration in the COPD subgroup, it is necessary to conduct studies with larger popu- lations.
Conclusions
This prospective, single center, double-blind, placebo-controlled, parallel group study demon- strated that the administration of NAC to COPD patients undergoing on-pump coronary artery surgery resulted in the preservation of pulmonary functions. However, it was also observed that NAC administration had no effect on other pul- monary parameters, on the duration of ventilato- ry support, and on the length of stay in the ICU.
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Conflict of Interest
The Authors declare that there are no conflicts of interest.
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